Induction of heat shock proteins (Hsps), a class of molecular chaperones, is a physiological and biochemical response to abrupt increases in temperature or exposure to a variety of other metabolic insults including heavy metals, amino acid analogs, toxins, and oxidative stress. This response occurs in all prokaryotic and eukaryotic cells and is characterized by repression of normal protein synthesis and initiation of transcription of Hsp-encoding genes. Under normal or nonstressed conditions, constitutively expressed Hsps facilitate proper protein folding and maturation, promote protein translocation across membranes, and regulate hormone receptor and protein kinase activity (Hightower, L. E., et al. (1991) Cell, 66:191-197).
During cellular stress, Hsps form a complex with proteins that misfold or unfold, either "rescuing" these proteins from irreversible damage or increasing their susceptibility to proteolytic attack. Overexpression of Hsps in transgenic mice and rats, or prior heat treatment of normal animals to induce Hsps, protects the heart muscle from ischemic injury. Both heat shock-induced and exogenous Hsps protect smooth muscle cells from serum deprivation-induced cell death. Overexpression of Hsps also protects murine fibroblasts from both UV light injury and proinflammatory cytokines released during UV exposure. Specific Hsps bind immunosuppressive drugs and may play a role in modulation of immune responses. Hsps expressed in cancer cells can protect the cancer cells from the cytotoxic effects of drugs used in anticancer therapies. Hsps isolated from tumor cells, when purified and used as antigens, have been shown to provide immunity to the tumors from which they are isolated (Udono, H., et al. (1994) J. Immunol. 152:5398-5403; Young R. A. (1990) Annu. Rev. Immunol. 8:401-420; Marber, M. S., et al. (1995) J. Clin. Invest. 95:1446-1456; Simon, M. M., et al. (1995) J. Clin. Invest. 95:926-933).
Several of the constitutive Hsp genes are located in the major histocompatibility complex on chromosome 6, and members of the Hsp family play roles in T-cell mediated regulation of inflammation and immune recognition. Hsps bind to steroid hormone receptors, repress transcription in the absence of the ligand, and provide the proper folding of the ligand-binding domain in the presence of the hormone. Heat shock treatment of B-cells enhances processing of antigen and the assembly and function of MHC class II molecules (Sargent, C., A. et al (1989) Proc. Natl. Acad. Sci. 86:1968-1972; Fang, Y., et al. (1996) J. Biol. Chem. 271:28697-28702; Hendrick, J. P., et al (1993) Proc. Natl. Acad. Sci. 90:10216-10220).
Knockout mice are providing additional information on the roles of Hsps. For example, female homozygous knockout mice for Hsp70 are found to undergo normal meiosis and are fertile. In contrast, the homozygous male knockout mice lack postmeiotic spermatids and mature sperm and are infertile (Dix, D. J. et al. (1996) Proc. Nat. Acad. Sci. 93:3264-3268).
Hsps function in a variety of necessary cellular processes including protein translocation across membranes of cell organelles, nascent protein folding and multiunit protein assembly, antigen presentation, protein degradation in the lysosome, and uncoating of clathrin-coated vesicles. They are located in all major cellular compartments and function as monomers, multimers, or in complexes with other cellular proteins, which may determine the rate and specificity of the Hsp action. The yeast and bacterial homologues of the human Hsp70 function as a complex with the DnaJ gene product to accelerating the rate of ATP hydrolysis during protein folding and protein complex assembly. Human homologues of the DnaJ protein have recently been characterized and are found be strongly induced by heat shock and to have sequence similarity with the DnaJ protein family. The DnaJ homologue, hsp40, was shown to colocalize with hsp70 in the nuclei and nucleoli of heat-shocked HeLa cells. Two other homologues, HSJ1a and HSJ1b, are expressed primarily in the human hippocampus and frontal cortex (Ohtsuka, K. (1993) Biocem. Biophys. Res. Com. 197:235-240 and Cheetham, M., E., et al. (1992) Biochem. J. 284:469-476).
The discovery of two new DnaJ-like proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer, inflammatory, and immune disorders.